Some cognitively intact elderly people have numerous cerebral amyloid deposits, a potentially benign form of senile cerebral amyloidosis referred to as "pathological aging"(PA). Other subjects with PA have cognitive impairment. The goal of this project is to determine the substrates of cognitive impairment in PA and to determine whether or not PA is preclinical AD. Clinicopathological analyses are used to determine if cognitive impairment correlates better with cytoskeletal and synaptic pathology than cerebral amyloid deposition, which is the hallmark of PA. Given that amyloid in PAD differs in several ways from that in AD, measures of heterogeneity of amyloid are included in quantitative assessments. Standardized histopathological, biochemical and morphometric measures are correlated with cross-sectional and longitudinal clinical measures. In particular, paired helical filament-tau (PF-tau), synaptic proteins and specific amyloid peptides are measured with ELISA. Amyloid and PHF-tau "burden" are also measured with the image analysis of tissue sections. Severely impaired subjects from EAS are supplemented with brain bank cases from Mayo Clinic Jacksonville to show that disease progression correlates with progressive PHF-tau accumulation and synapse loss, rather than amyloid deposition. All correlations are made with respect to apolipoprotein-A genotype. Similar assays as those used for "pure" AD and PA cases are performed on brains with "mixed" pathology, including cases with Lewy bodies and vascular disease. Multivariate statistical methods are used to determine the relative contribution of various pathological indices to cognitive function. A second and related aim is to use postmortem information to refine clinical criteria for Lewy body dementia and hippocampal sclerosis, common findings in brains of demented elderly with PA. Finally, in those brains with no significant pathology, clinicopathological correlates of cognitive slowing will be performed by analysis of inevitable age-relate granular degeneration of myelin. Imaging analysis and immunoassays for ubiquitin will be correlated with antemortem measures of cognitive processing speed.